The vast amount of structural and kinetic data available for the ribosome makes it the ideal system for investigating the physical-chemical properties that enable biological dynamics. Through the use of simplified models and explicit-solvent simulations, we are probing the balance between structural flexibility and energetics during large-scale conformational transitions. Explicit-solvent simulations (200ns - 1.3 microseconds) are used to obtain diffusion coefficients, which help provide a quantitative relationship between tRNA movement, large-scale rotary motions and the energetic barriers encountered during function. To complement explicit-solvent calculations, all-atom simulations that employ simplified energetic descriptions allow us to determine the relative contributions of configurational entropy and sterics. Together, these calculations provide a theoretical foundation that quantitatively bridges experimental kinetics, single-molecule measurements, structural/mutational data and theoretical calculations.